PHARMACY POLICY 5.01.548

Pharmacotherapy of Cushings Disease and Acromegaly

Effective Date: Dec. 1, 2017

Last Revised: Nov. 21, 2017

Replaces: N/A

RELATED POLICIES:

None

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POLICY CRITERIA | CODING | RELATED INFORMATION

EVIDENCE REVIEW | REFERENCES | HISTORY

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Introduction

The pituitary gland is about the size of a pea. Its just behind the bridge of the nose and is

attached to the brain with nerve fibers. Despite its small size, it plays a very large role in

controlling other glands throughout the body. For this reason, the pituitary is often called the

master gland. The pituitary gland also produces other hormones, including ACTH and growth

hormone. In Cushings disease, a pituitary tumor causes the pituitary gland produce too much

ACTH. The ACTH then signals the adrenal glands to produce cortisol. Removing the tumor often

allows the pituitary gland to return to producing normal levels of ACTH, which then lowers the

cortisol levels. Acromegaly is a condition that results in enlargement of the hands, feet, and face.

Its caused by the pituitary gland producing too much growth hormone. A noncancerous tumor

on the pituitary gland is the most common cause acromegaly. Specific drugs may be used to

treat Cushings disease or acromegaly when surgery or other medications didnt work or cant

be used. This policy describes when specific drugs to treat these conditions may be considered

medically necessary.

Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The

rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for

providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can

be a place where medical care is given, like a hospital, clinic, or lab. This policy informs them about when a

service may be covered.

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Policy Coverage Criteria

Drug Medical Necessity Signifor (pasireotide)

and Korlym

(mifepristone)

Signifor (pasireotide) and Korlym (mifepristone) may be

considered medically necessary for treatment of Cushings

disease when ALL of the following conditions are true:

Patient has failed transsphenoidal surgery (TSS), is not a

surgical candidate or has failed surgery

AND

Patient has failed a trial of bromocriptine or cabergoline, unless

contraindicated or otherwise medically inappropriate

AND

Patient has failed a trial of metopirone or mitotane, unless

contraindicated or otherwise medically inappropriate.

All other uses of Signifor, Signifor LAR (pasireotide) and

Korlym (mifepristone) are considered investigational.

Signifor LAR

(pasireotide)

Signifor LAR (pasireotide) may be considered medically

necessary for the treatment of acromegaly when the following

condition(s) is/are met:

Patient has had an inadequate response to surgery

AND/OR

Surgery is not an option.

Coding

Code Description

HCPCS

J2502 Injection, pasireotide (Signifor) long acting, 1 mg

Note: CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS

codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

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Related Information

Benefit Application

This policy is managed through the Pharmacy benefit.

Evidence Review

Description

Cushings syndrome is a classic constellation of symptoms caused by long-term exposure to

excessively high levels of circulating corticosteroid hormones. The most common cause of

Cushings syndrome is exogenous glucocorticoid administration. However, symptoms may result

from endogenous causes including ACTH-dependent and ACTH-independent Cushings. ACTH-

dependent disease makes up 80% of endogenous cases and is due to pituitary adenoma in 85%

of cases and ectopic tumor secretion in 15% of cases. Cushings disease refers to pituitary

tumors that secrete ACTH.

Cushings syndrome occurs in 1-3 patients/million persons yearly with a prevalence of 40

cases/million persons, more frequently in females (3:1). Cushings disease occurs more rarely

than Cushings syndrome and incidence peaks in the third to fourth decade.

The pituitary produces many hormones including TSH, growth hormone, ACTH, luteinizing

hormone, follicle stimulating hormone, prolactin, and vasopressin. Pituitary adenomas can result

in overproduction of ACTH, resulting in excess cortisol production from the adrenal glands. The

hypothalamic-pituitary-adrenal (HPA) axis no longer retains its circadian rhythm and

hypercortisolism occurs. Excess cortisol results in a wide constellation of symptoms including

truncal obesity, hypertension, impaired glucose tolerance, dyslipidemia, increased risk of arterial

thrombosis, psychiatric and cognitive disorders, osteoporosis, muscle and skin atrophy, impaired

immune function, and hyperandrogenism. Quality of life (QOL) is frequently impaired. Morbidity

and mortality is increased due to increased infections as well as cardiovascular disease resulting

from increased cardiovascular risk factors such as hypertension, DM, and dyslipidemia.

Estimated 5-year survival in untreated patients is 50%. With treatment, chances of death remain

2-4 times greater than the average population.

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Treatment Alternatives for Cushings disease

The preferred treatment for Cushings disease transsphenoidal surgery (TSS), which results in

long-term remission rates of 60-90% with a recurrence risk of 26% within 10-years. Poor

outcomes are seen with larger tumor size and repeat surgeries. Patients with persistent disease

after surgery can be treated with pituitary irradiation; however, months to years of treatment

may be required before an effect is seen. Bilateral adrenalectomy may also be performed;

however, the pituitary adenoma remains in situ, negative feedback effects of cortisol are lost,

and replacement gluco- and mineralocorticoids are required.

Medical therapy is used with unsuccessful surgery, patients without an adenoma image on MRI,

those undergoing radiotherapy which is not yet effective, patients with severe complications of

Cushings, and with those ineligible for surgery. Cushings disease can be treated with drugs that

target the adenoma, adrenal ACTH receptors or glucocorticoid receptors. Drugs which target the

pituitary include somatostatin analogs and dopamine agonists bromocriptine and cabergoline.

Cabergoline is a dopamine agonist that targets dopamine receptor subtype 2 (D2R), which is

expressed in 80% of ACTH-secreting pituitary adenomas.

Adrenal-targeting drugs include ketoconazole, metopirone, and mitotane. These agents act by

inhibiting steroid formation. Ketoconazoles actions are linked to inhibition of CYP 450 enzymes.

Mitotane is typically effective in >50% of cases while ketoconazole and metopirone are effective

in approximately 50% of patients. Mifepristone is the only agent available which blocks

glucocorticoid receptors, more specifically the cortisol and progesterone receptors. Mifepristone

is FDA indicated for patients with Cushings syndrome with diabetes or glucose intolerance that

require glycemic control. Each of these agents, with the exception of pasireotide, has been

evaluated in a small number of patients. All except pasireotide and mifepristone are not FDA

indicated for Cushings disease or syndrome. (NOTE: FDA has issued a warning against

ketoconazole use because of case reports of potentially fatal liver injury. For this reason, its use

in Cushings disease is no longer recommended.)

Although several different guidelines address the diagnosis of Cushings disease, few address

medical treatment. The European Neuroendocrine Association and the Pituitary Society last

published a consensus statement in 2008 which discussed therapy options as described above.

The guidelines emphasized the importance of surgery as a first line option, but did not

recommend any particular medical therapy above another.

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Treatment Alternatives for Acromegaly

The goals of therapy are to lower the serum insulin-like growth factor 1 (IGF-1), and serum

growth hormone (GH) concentrations. For a patient who has microadenoma/macroadenoma,

which is resectable, transsphenoidal surgery is preferred. If adenoma is not resectable (or patient

is not a candidate for surgery), then the preferred treatment would be a long-acting

somatostatin analog, such as octreotide or lanreotide. If somatostatin analog treatment with or

without cabergoline is not effective, adding pegvisomant may be necessary (note this approach

has NOT been approved by the FDA). If adenoma size keeps increasing despite the use of

somatostatin analog with pegvisomant, radiotherapy or repeat surgery may be warranted.

Pasireotide

Pasireotide is a cyclohexapeptide somatostatin analogue. Pasireotide binds to and activates

somatostatin receptors. This results in the inhibition of ACTH, leading to decreased cor